Expression of HPV oncogenes from a single integration site in cervical cancer cell lines

Integration of a virus genome into human chromosomal DNA is critical in viral carcinogenesis. In this report, we discovered that virus-host fusion transcripts are characteristically originated mainly from a single integration site in three cervical cancer cell lines, CaSki and SiHa cells with multiple HPV16 DNA integration sites and HeLa cells with multiple HPV18 DNA integration sites. The host genomic elements surrounding the integrated HPV genome are critical for efficient expression of the viral oncogenes. We found that HPV E6 and E7 are expressed by hijacking a host 3’ splice site and/or RNA polyadenylation signal for their production. The viral-host fusion transcripts may encode a chimeric viral-host fusion protein through alternative RNA splicing. One such E6* protein in SiHa cells was found to antagonize E6 function and knockdown of its expression further decreased p53 protein level and increased cell growth by promoting S phase entry. Together, our findings of the integrated virus genome expression only from a given integrated host genomic site will shed new light on possible application of precision medicine and the understanding of HPV carcinogenesis.